The most frequent question that patients ask at the time of diagnosis of antl-neutrophil cytoplasmic autoantibody (ANCA) disease Is what caused my disease? Currently, we are studying the Immunopathogenesis of ANCA disease from the perspective of the autoantibody. Now we turn our attention to epigenetic regulation of the autoantigens and to genes that modify disease phenotype. Aim 1 builds on our discovery that mature, multi-lobed peripheral neutrophils from patients are expressing PR3 and MPO transcripts normally seen only In Immature bone marrow cells. We have shown that loss of RUNX3 suppressor function is linked with loss of methylation status of histone H3K27, a quintessential histone modification involved in epigenetic gene silencing. Further, we know that the environmentally responsive histone demethylase, JumonjI D3, is Increased In patients. We will explore whether there Is an epigenomic signature that predisposes patients to ANCA disease. Genetically modified mice will be used to explore how RUNX3, the histone methyltransferase Enhancer of Zeste 2, and JumonjI D3 regulate neutrophil gene expression. Finally, we will study the fate of aberrant transcripts of the autoantigen including sense and antisense transcripts. The results of this aim will focus attention on epigenetic regulation of the critical autoantigen genes as Important to the etiology of ANCA disease. In Aim 2 we focus our attention on specific genes that modify the phenotype of ANCA disease. Genes Implicated in modifying phenotype in other autoimmune diseases will be tested for association with subgroups of ANCA disease patients, based on the hypothesis that these genes will modulate the phenotype of ANCA disease. New candidate genes. Identified in a mouse genome wide screen for quantitative trait loci, will be examined for alleles that associate with ANCA disease. Finally, genome wide association studies comparing genotypes of ANCA cases versus healthy controls, and ANCA patients with good versus poor outcomes will uncover genetic loci that govern disease susceptibility and prognosis. Uncovering genetic influences of ANCA disease will make strides towards the ultimate goal of answering the question of what causes ANCA disease.